Exam 4 Review:  Chapter 25:  Renal Tubular Physiology

tubular reabsorption - The complex set of physiological processes, primarily involving specific primary and secondary active transport mechanisms, which accomplishes the return of a wide variety of physiologically and nutritionally important ions or molecules, e.g., water (~99% of the water entering the filtrate), electrolytes, nutrients, vitamins, regulatory substances, and certain proteins, from the plasma filtrate as it passes along the tubule system (the proximal convoluted tubule, where the majority of tubular reabsorption occurs, the loop of the nephron, the distal convoluted tubule, and collecting ducts) of the nephron in the kidney; ultimately, the transport is powered by ATP hydrolysis; the regulation of this process is influenced by a variety of hormones including the renin-angiotensin system, aldosterone, antidiuretic hormone (ADH) = vasopressin, atrial natriuretic peptide = ANP, parathyroid hormone = parathormone = PTH, and calcitonin = thyrocalcitonin.

primary active transport - The movement of ions or molecules, e.g., a Na+ ion or a glucose, through a cell membrane, usually along a gradient of concentration or electrical potential in the direction opposite to normal diffusion, requiring the direct expenditure of energy in which ATP hydrolysis occurs at the same site as the movement of the ions or molecules through the membrane; a variety of membrane-bound proteins have this capacity, e.g., ion pumps, symporters, and antiporters.

Animation of a simple primary active transport mechanism:

secondary active transport - The movement of ions or molecules, e.g., a Na+ ion or a glucose, through a cell membrane, usually along a gradient of concentration or electrical potential in the direction opposite to normal diffusion, requiring the indirect expenditure of energy in which ATP hydrolysis occurs at a different site (often a primary active transport system such as a Na+/K+ ATPase transport system) from the movement of the ions or molecules through the membrane; a variety of membrane-bound proteins have this capacity, e.g., ion pumps, symporters, and antiporters.

Animation of a secondary active transport mechanism:  To the right is the Na+/K+ ATPase pump which transports 3 Na+ ions out of the cell and 2 K+ ions into the cell with each ATP hydrolysis. This creates a concentration gradient for sodium (higher concentration outside the cell than inside) which drives the secondary transport of a glucose (an example of a symporter on the left) in conjunction with the movement of Na+ ions along its concentration gradient.

symporter - A type of active transport protein found in cell membranes which moves two different ions or molecules, e.g., a Na+ ion and a glucose, in the same direction across the membrane; often one ion or molecule can be moved in opposition to its concentration gradient because the movement of the other ion or molecule, moving in accord with its concentration gradient, is driving the process; ultimately, the movement is powered by ATP hydrolysis, but that energy source may be directly (primary active transport) or indirectly (secondary active transport) associated with the active transport protein.

transport maximum (Tm) - The upper limit on the speed of any membrane transport protein (symporter or antiporter); in the nephron, any time a substance is in the plasma filtrate in an amount greater than its transport maximum (Tm), some of that substance will be left behind in the urine; only Na+ has no transport maximum (Tm) because Na+ is being actively transported by the Na+/K+ ATPase pump at all times.

renal threshold - The plasma concentration at which a substance begins to spill into the urine because its transport maximum (Tm) has been surpassed; if the plasma filtrate concentration of a given substance is too high, then all of the substance cannot be reabsorbed; e.g., glucose spills into the urine (glycosuria) in untreated diabetics when plasma glucose levels exceed ~400 mg/100mL because the transport maximum (Tm) for glucose is ~375 mg/min.

tubular secretion -  The complex set of physiological processes, primarily involving specific primary and secondary active transport mechanisms, which accomplishes the removal of a variety of physiologically significant ions or molecules, which are either metabolic wastes (H+, nitrogenous wastes, etc.), electrolytes ingested in excess of body needs (K+, HPO4-2, SO4-, etc.), or toxins (including many drugs), from the blood plasma into the filtrate/urine as it passes along the tubule system (the proximal convoluted tubule, the loop of the nephron, the distal convoluted tubule, where the majority of tubular secretion occurs, and the collecting ducts) of the nephron in the kidney; ultimately, the transport is powered by ATP hydrolysis; the regulation of this process is influenced by a variety of hormones including the renin-angiotensin system, aldosterone, antidiuretic hormone (ADH) = vasopressin, atrial natriuretic peptide = ANP, parathyroid hormone = parathormone = PTH, and calcitonin = thyrocalcitonin. 

antiporter - A type of active transport protein found in cell membranes which moves two different ions or molecules, e.g., a Na+ ion and a glucose, in opposite directions across the membrane; often one ion or molecule can be moved in opposition to its concentration gradient because the movement of the other ion or molecule, moving in accord with its concentration gradient, is driving the process; ultimately, the movement is powered by ATP hydrolysis, but that energy source may be directly (primary active transport) or indirectly (secondary active transport) associated with the active transport protein.

Na+/K+ ATPase - an integral membrane protein active transport molecule which has the capacity to bind and hydrolyze ATP and use the energy from the ATP hydrolysis to move 3 Na+ ions from the cytoplasm to the exterior of the cell while simultaneously moving 2 K+ ions from the exterior of the cell into the cytoplasm; the action of this ion pump is the main factor in establishing a resting membrane potential for the cell.

urea - A highly water-soluble, non-toxic compound, CO(NH2)2, formed from the addition of two amino groups (-NH2) to a molecule of carbon dioxide (CO2) in the liver, which is the major nitrogenous waste product of protein catabolism and is the chief nitrogenous waste component of the urine.

carbonic anhydrase - An enzyme found in erythrocytes (RBCs) and renal tubular epithelial cells which catalyzes the reversible reaction in which carbon dioxide and water combine to form carbonic acid; it is an enzyme with great catalytic efficiency so it can be present in very low concentration and still be effective.  [Note:  Carbonic acid spontaneously dissociates into hydrogen ion and bicarbonate ion at normal body fluid pH.]

                                        (carbonic anhydrase)

    CO2             +     H2O <============> H2CO3 <============> H+         +     HCO3-  

carbon dioxide +     water                            carbonic acid                       hydrogen ion + bicarbonate ion 


bicarbonate ion = HCO3- - The anion, HCO3-, formed from the dissociation of carbonic acid, H2CO3, which is an important body fluid buffer; the concentration of bicarbonate ions is regulated by both the respiratory system and the kidneys; the concentration of bicarbonate ions in the blood is the major indicator of the buffering capacity of the blood at any given moment.

List:

5. the molecular and cellular sequence of events involved in secondary active transport as is used for reabsorption and secretion of some substances by nephron tubule cells.
 
(1) Na+/K+ ATPase pumps on the interstitial face of the renal tubular cells operate continuously, creating a concentration gradient for sodium, with less sodium inside the renal tubular cells, and creating a concentration gradient for potassium, with less potassium outside the renal tubular cells.  Each time the Na+/K+ ATPase pump operates, powered by an ATP hydrolysis, 3 sodium ions are removed from the cytoplasm and 2 potassium ions are moved into the cytoplasm.
(2) However, potassium leakage channels on the interstitial face of the renal tubular cells allow the potassium to escapte back outside the renal tubular cells.
(3) Some of these sodium and potassium ions will be picked up by the blood in the peritubular capillaries and be returned to the systemic circulation.
(4) More importantly, in terms of secondary active transport, the sodium concentration gradient may be used to power a wide variety of secondary active transport mechanisms, using symporters or antiporters.
Symporters (see illustration below):  Symporters will be located in the luminal face of the renal tubular cells.  One of the symporter binding sites will be designed for sodium ions; the other binding site will be for some substance the body would like to conserve, e.g., glucose, amino acids, certain electrolytes, some vitamins, etc.
Each time the Na+/K+ ATPase pump operates, powered by an ATP hydrolysis, 3 sodium ions are removed from the cytoplasm, and these 3 sodium ions can be replaced by drawing them from the plasma filtrate in the renal tubule lumen.  The 3 sodium ions will move, one at a time, from the lumen into the renal tubular cell cytoplasm, aided by the symporter.  However, the symporter will only operate if the other binding site is also occupied.  Therefore, each time a sodium is drawn inside from the tubular lumen, following the sodium concentration gradient established by the continuing action of the Na+/K+ ATPase pumps, a molecule of the other substance is also transported from the plasma filtrate back to the cytoplasm of the renal tubular cell.
Once inside, the other substance will diffuse across the interstitial face of the renal tubular cells and into the interstitial fluid.  From there, again, following its concentration gradient, it will diffuse into the blood in the peritubular capillaries and be returned to the systemic circulation.
The only ATP expenditure in this process is the ATP hydrolysis associated with the continuing action of the Na+/K+ ATPase pumps on the interstitial face of the renal tubular cells.
Antiporters Antiporters operate in a similar fashion.  The difference with an antiporter is that when a sodium ion is bound the antiporter on the luminal surface, some other substance the body would like to eliminate, e.g.,  potassium, hydrogen, sulfate or phosphate ions, urea, uric acid, etc., will bind to the cytoplasmic surface of the antiporter.  then, once both sites are occupied, the antiporter will act, transporting the sodium into the cytoplasm and the "waste" molecule into the filtrate/urine.

Sketch and label:

4. a simple illustration of a Proximal Convoluted Tubule cell (PCT cell) and label the components that illustrate the basic mechanism of secondary active transport used to reabsorb or secrete substances in the nephron.

See the discussion in List: Q4 above for the basic mechanism of secondary active transport.  Your illustration should include the following labelled components:  (1) tubule lumen, (2) renal tubular cell, (3) interstitial fluid, (4) peritubular or vasa recta capillary, (5) Na+/K+ ATPase pump or Na+ ATPase pump in the membrane of the interstitial face of the renal tubular cell, (6) sodium ions, and (7) an example of either a symporter or an antiporter in the membrane of the lumenal face of the renal tubular cell and (8) the substance being secondarily actively transported.
Symporter Antiporter

Describe:

3. three mechanisms by which the nephron can regulate the pH of the blood. Make a simple sketch of how these processes occur in the PCT and DCT of the nephron and in the collecting ducts.

 
(1)  In the Proximal Convoluted Tubule (PCT), Na+/H+ antiporters move H+ ions directly into the filtrate.  H+ ions combine with HCO3- ions in the filtrate to form CO2 and H2O.

(2)  In the PCT, CO2 from the filtrate or from the cell cytoplasm or the interstitial fluid can combine with H2O (in the active site of carbonic anhydrase or spontaneously) to form carbonic acid H2CO3.  Carbonic acid H2CO3 will then dissociate into H+ ions and HCO3- ions.  The H+ ions may be actively transported to the filtrate in the lumen while the HCO3- bicarbonate ions can move in the opposite direction, following passively as sodium ions are pumped actively back to the interstitial space where will they will diffuse into the blood in the peritubular or vasa recta capillaries and be returned to the systemic circulation.

(3)  In the collecting ducts, H+ ATPase pumps actively transport H+ ions into the urine.  The Distal Convoluted Tubule (DCT) plays only a very minor role in adjustment of blood/filtrate pH.

The Figures below illustrate processes of the PCT.

Explain:

5.  the molecular mechanisms which operate in the renal tubule to secrete H+ ions and reabsorb bicarbonate ions and give their specific locations.

          (1)  In the Proximal Convoluted Tubule (PCT), Na+/H+ antiporters move H+ ions directly into the filtrate.  H+ ions combine with HCO3- ions in the filtrate to form CO2 and H2O.

          (2)  In the PCT, CO2 from the filtrate or from the cell cytoplasm or the interstitial fluid can combine with H2O (in the active site of carbonic anhydrase or spontaneously) to form carbonic acid H2CO3.  Carbonic acid H2CO3 will then dissociate into H+ ions and HCO3- ions.  The H+ ions may be actively transported to the filtrate in the lumen while the HCO3- bicarbonate ions can move in the opposite direction, following passively as sodium ions are pumped actively back to the interstitial space where will they will diffuse into the blood in the peritubular or vasa recta capillaries and be returned to the systemic circulation.

          (3)  In the collecting ducts, H+ ATPase pumps actively transport H+ ions into the urine.

 
6. the three basic mechanisms of regulating blood pH.

          (1)  Body fluids contain a wide variety of buffering substances including proteins, bicarbonate ions, and phosphate ions.  Buffers form chemical bonds with H+ ions which neutralize them for as long as they are associated with the buffers.

          (2)   Exhalation of breath reduces CO2 content in the blood.  This reduction in pCO2 indirectly reduces H+ ion concentration in the blood because some of the carbon dioxide is generated as a result of  the synthesis of carbonic acid from H+ and bicarbonate ions .  This reaction occurs spontaneously but can also be catalyzed by the enzyme carbonic anhydrase which is present in erythrocyte cytoplasm.  [See the chemical reaction in the definition for carbonic anhydrase above.]

          (3)   The kidney is capable of actively transporting large quantities of H+ ions into the urine by means of several molecular mechanisms.

7. what the term compensation means in relation the regulating pH in the body.

Compensation is defined as the increase in size or activity of one part of an organism or organ which makes up for the loss or dysfunction of another part.

In terms of acid-base derangements, the first line of defense against disturbances in pH are the intra- and extracellular buffering systems which minimize the change in pH; in more serious situations, additional mechanisms to resist further changes in pH are respiratory adjustments of extracellular fluid (ECF) PCO2 and renal adjustments of ECF HCO3- concentration.

Such adjustments for acid-base imbalance are only partially effective; perfect compensation, without correcting the underlying cause of the pH disturbance, is not possible because it would remove the stimulus for the compensatory mechanisms and the imbalance would be re-established; furthermore the compensatory mechanisms act not only to minimize changes in the pH but also operate, after correcting the cause of the pH disturbance, to restore the body's buffer reserves leaving it more able to cope with repeated episodes of acid-base disturbance.

In simpler terms, if the cause of an acid-base imbalance in the body is due to respiratory problems (hyperventilation or hypoventilation), then the kidney will compensate by attempting to excrete more or less hydrogen ions as appropriate.  If the cause of an acid-base imbalance in the body is due to metabolic problems (a much longer list of diverse disorders), then the respiratory system will compensate by attempting to exhale more or less carbon dioxide as appropriate.  Recall that hyperventilation or hypoventilation indirectly affect blood pH.  [See the acid-base balance review materials for Chapter 26 also.]